Development of a safe, practical and effective HIV-1 vaccine is one of the highest priorities of the global scientific community (Klausner et al, Science 5628:2036-2039 (2003); Esparza et al, Science Strategic Plan, DOI: 10.1371/journal.pmed.0020025, Policy Forum Vol. 2, February 2005)). While anti-retroviral treatment (ART) has dramatically prolonged the lives of HIV-1 infected patients, anti-retroviral therapy is not yet routinely available in developing countries, and the global rate of spread of HIV-1 continues unabated.
There are multiple components for successful HIV vaccine development. First is the production of HIV envelope constructs that express neutralizing epitopes reflective of the native envelope (Env) to ensure that the regions and epitopes to which it is desired to induce protective antibodies are indeed present on the Env immunogen (i.e., envelope antigenicity). Second, for scalablility of Env protein production, it is important to be able to make monomeric Envs that are not disulfide linked. The Sodroski laboratory has previously shown that when gp120 Envs are produced in 293T mammalian cells, there is nearly always a major component of the Env that is disulfide linked (Finzi A, Pacheco B, Zeng, X, Young D K, Kwong, P D, Sodroski, J, J. Virol. Methods 168: 155-161, 2010). This disulfide linked Env has many of the desired epitopes occluded and not available for antibody binding (Finzi A, Pacheco B, Zeng, X, Young D K, Kwong, P D, Sodroski, J, J. Virol. Methods 168: 155-161, 2010). Third, many of the regions of the HIV Env are poorly immunogenic or the responses to these epitopes are down regulated by tolerance mechanisms or represent rare maturation pathways (i.e., are subdominant in nature) (McElrath J, Haynes, B F, Immunity 33:542-54. 2010; Verkoczy L, Kelsoe, G, Moody, M A, Haynes, B F, Current Opinion in Immunology 23:383-390, 2011).
The first and second components described above can be dealt with by immunogen design. The third component is dealt with by taking an optimally antigenic Env and formulating it with appropriate adjuvants to drive an otherwise subdominant antibody response in an immunodominant manner by design of immunogens that can optimally trigger naïve B cell receptors of clonal lineages that can make protective antibodies (Ma, B J, Alam, S M, Go, E P, Lu, X, Desaire, H, Tomaras, G D, Bowman, C, Sutherland, L L, Scearce, R M, Santra, S, Letvin, N L, Kepler, T B, Liao, H X, Haynes, B F, PLoS Pathogens, in press, 2011).
The present invention relates, at least in part, to a gp120 Env design strategy that addresses the first two components of the HIV-1 vaccine problem referenced above: optimal antigenicity and stable gp120 monomer production for scalability of vaccine production.